Cholecystokinins (CCK) are a family of polypeptide hormones. CCK and a 33 amino acid fragment of CCK (CCK.sub.33) were first isolated from hog intestine. (Mutt and Jorpes, Biochem. J., 125,628, 1981). Recently the CCK.sub.33 fragment has been found in the brain, where it appears to be the precursor of two smaller fragments, an octapeptide CCK.sub.8 and a tetrapeptide CCK.sub.4 (Dockray, Nature, 264, 4022, 1979).
CCK.sub.8, the carboxyl terminal octapeptide fragment of CCK, is the smallest CCK fragment that remains fully biologically-active. (Larsson and Rehfeld, Brain Res. 165,201-218, 1979). The localization of CCK fragments in the cortex of the brain suggests that CCK may be an important neuromodulator of memory, learning and control of primary sensory and motor functions. CCK and its fragments are believed to play an important role in appetite regulation and satiety. (Della-Fera, Science. 206,471, 1979; Gibbs et al., Nature, 289, 599, 1981; and Smith, Eating and Its Disorders, Raven Press, New York, p. 67, 1984).
CCK antagonists (B. J. Gertz in Neurology and Neurobiology, Vol 47, Cholecystokinin Antagonists, Wang and Schoenfeld, eds., Alan R. Liss, Inc., New York, N.Y., pp. 327-342, 1988; Silverman et al., Am J Gastroent, 82(8), 703-8, 1987) are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal (GI) (Lotti et al., J. Pharm Exp Therap, 241(1), 103-9, 1987), central nervous (CNS) (Panerai et al., Neuropharmacology, 26(9), 1285-87, 1987) and appetite regulatory systems of animals, especially man. CCK antagonists are also useful in potentiating and prolonging opiate induced analgesia and thus have utility in the treatment of pain. (Faris et al., Science 226, 1215, 1984; Rovati et al., Clinical Research, 34(2), 406A, 1986; Dourish et al., European J. Pharmacology, 147, 469-72, 1988). Disease states that may be treated with CCK antagonists are disorders of gastric emptying, gastroesophageal reflux disease (Setnikar et al, Arzn Forsch./Drug Research, 37(II) 10, 1168-71, 1987), pancreatitis, pancreatic and gastric carcinomas (Douglas et al., Gastroent, 96, 4629, 1989; Beauchamp et al., Am Surg. 202, 313-9, 1985), disorders of bowel motility, biliary dyskinesia, anorexia nervosa, hypoglycemia (Rossetti, Diabetes, 36, 1212-15, 1987; Reagan, European J. Pharmacology, 144, 241-3, 1987), gallbladder disease, and the like.
Previously four distinct chemical classes of CCK receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides as represented by dibutyryl cyclic GMP (Barlos et al., Am, J. Physiol., 242, G161, 1982) and references sited therein). The second class is represented by the C-terminal fragments of CCK (see Jensen et al., Biochem. Biophys. Acta, 757, 250 1983) and Spanarkel, J. Biol. Chem. 258, 6746, 1983). The third class comprises amino acid derivatives of glutamic acid and tryptophan as indicated by proglumide (and its analogs) and benzotript, very simple analogs of CCK (see Hahne et al., Proc. Natl. Acad, Sci. U.S.A., 78, 6304, 1981 and Jensen et al., Biochem. Biophys. Acta. 761,269, 1983). The fourth and most recent class is comprised of 3-substituted benzodiazepines, represented by L-364,718 (see: Evans et al., Proc. Natl, Acad, Sci, U.S.A., 83 4918, 1986).
With the exception of certain substituted benzodiazepines and recently reported analogs of proglumide (Makovec et al., Arzneim.-Forsch./Drug Res. 36,(I), 98-102, 1986; European Patent Application No. 0,272,228; PCT Patent Application No. WO 88/05774), all of these compounds are relatively weak antagonists of CCK usually demonstrating IC.sub.50 's between 10.sup.-4 and 10.sup.-6 M. The benzodiazepine CCK antagonists or their metabolites may have undesirable effects in vivo due to their interaction with benzodiazepine or other receptors.
The C-terminal pentapeptide fragment of CCK is the same as the C-terminal pentapeptide fragment of another polypeptide hormone, gastrin Gastrin, like CCK, exists in the GI system. Gastrin antagonists are useful in the treatment and prevention of gastrin related disorders of the GI system such as ulcers, Zollinger-Ellison syndrome and central G cell hyperplasia. There are no effective receptor antagonists of the in vivo effects of gastrin. (Morely, Gut Pept. Ulcer Proc., Hiroshima Symp. 2nd, 1, 1983). A recent report (Bock J. Med. Chem., 32, 13-16, 1989) discloses potent in vitro gastrin antagonists.
Analogs of proglumide have also been disclosed by Freidinger (U.S. Pat. 4,860,938) and Nadzan and Kerwin (U.S. Pat. No. 4,971,978), but both require a carboxylate or carboxyalkyl terminal group, respectively, and neither possesses the novel combinations of activity and selectivity of the instant invention.